Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
may be found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Hofle, G., et al., Angew. Chem. Int. Ed. Engl., Vol. 35, No.13/14, 1567–1569 (1996); WO93/10121 published May 27, 1993; and WO97/19086 published May 29, 1997.
The widespread interest in epothilones that originated with the discovery of their mircotubulin-stabilization activity was furthered by the finding that epothilones were active in vitro against a number of paclitaxel-resistant human cancer cell lines (Bollag, D. M., et al., Cancer Res., Vol. 55, 2325–2333 (1995); Kowalski, R. J., et al., J. Biol. Chem., Vol. 272, 2534–2541 (1997)). Additionally, the relatively efficient total synthesis of epothilones, compared to that of paclitaxel, has lead to extensive efforts in the synthesis of epothilone analogs, as well as the characterization of their biological activity and structure/activity relationship (SAR) features. (Altmann, K.-H., et al., Curr. Opin. Chem. Biol., Vol. 5, 424–431 (2001)).
Several groups have been active in this area including Danishefsky at the Memorial Sloan-Kettering Cancer Research Center, Nicolaou at the Scripps Research Institute, Altmann at Novartis Pharma AG and Klar at Shering AG. For example, the Danishefsky group has prepared and characterized the biological activity of 12,13-desoxyepothilone derivatives (Chou T.-C. et al., Proc. Natl. Acad. Sci., Vol. 95, 9642 (1998)). The Nicolaou group at the Scripps Research Institute has synthesized 12,13-cyclopropyl, 12,13-cyclobutyl and related pyridine side-chain epothilone analogs. (Nicolaou, K. C., J. Amer. Chem. Soc., Vol. 123, 9313–9323 (2001)). Epothilone derivatives containing 16-halo substitutions have been prepared by the group at Schering AG (WO 00/49021). Additionally, Altmann at Novartis Pharma AG has synthesized an epothilone analog in which the thiazole moitey is conformationally locked by a benzenoid functionality (Altmann, K. H. et al., Chimica, Vol. 54, No. 11,612–621 (2000)).
Derivatives and analogs of Epothilones A and B have been synthesized and may be used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Angew. Chem. Int. Ed. Engl., Vol. 35, No.13/14, 1567–1569 (1996); Nicolaou, K. C., et al., Angew. Chem. Int. Ed. Engl., Vol. 36, No. 19, 2097–2103 (1997); Su, D. S., et al., Angew. Chem. Int. Ed. Engl., Vol. 36, No. 19, 2093–2097 (1997); Su, D. S., et al., Angew. Chem. Int. Ed. Engl., Vol. 36, 757–759 (1997); Meng, D., et al., J. Amer. Chem. Soc., Vol. 119, 10073–10092 (1997); Yang, Z., et al., Angew. Chem. Int. Ed. Engl., Vol. 36, 166–168 (1997); Nicolaou, K. C., et al., Angew. Chem. Int. Ed. Engl., Vol. 36, 525–527 (1997); Nicolaou, K. C., et al., Nature, Vol. 387, 268–272 (1997); Schinzer, D., et al., Angew. Chem. Int. Ed. Engl., Vol. 36, 523–524 (1997); and Nicolaou, K. C., et al., Angew. Chem. Int. Ed. Engl., Vol. 37, 2014–2045 (1998).
Although natural product epothilones A and B have shown excellent in vitro cytotoxic activity against cancer cell lines, difficulties remain with respect to their in vivo use due to a lack of stability, including metabolic stability, and potential toxicity (Lee, F., et al., Clin. Can. Res., Vol. 7, 1429–1437 (2001)). Thus, there remains a need in the art for biologically active epothilone compounds with improved in vivo stability and improved safety profiles.